Review Article Cardiomyopathy in Young Adults

Introduction
Cardiomyopathy are commonly divided into three types: dilated, hypertrophic and restrictive forms. The estimated prevalence of dilated cardiomyopathy is 920 cases per 100,000 persons, 50 to 200 cases per 100,000 persons of hypertrophic cardiomyopathy while restrictive cardiomyopathy is the rarest encountered form1. In young adults, peripartum cardiomyopathy constitutes a rare but potentially life-threatening condition when left untreated. In this review article, we will present an overview of peripartum cardiomyopathy, its management, prognosis and prevention.

Case illustration
A 33 year old female was brought to the hospital because of her generalized edema and shortness of breath. The patient history reveals that the symptoms originated 5 months earlier. At 5 months postpartum, an ulcer appeared on the anterior medial left leg. The ulcer was red, tender and oozing clear liquid. She was taken to the nearest health clinic where she was diagnosed with diabetes mellitus and discharged with sugar pills, the names of which the patient could not recall. However, the ulcer remained unchanged. Financial difficulties had hindered the patient from seeking medical care and by the fourth month of illness, the edema had spread to both of her upper and lower extremities along with a new onset of dyspnea. At this point, she was taken to a hospital in order to receive treatment. Medical history reveals that the patient was diagnosed with gestational hypertension at the second trimester of pregnancy. Tetanus vaccination status has never been administered. The patient and family denied a history of seizure or hemorrhage during labor. She gave birth at 36 weeks of gestation to a viable 3,3kg male infant who is healthy and thriving presently. On the eleventh month postpartum, patient was taken to the hospital and a full investigation was performed. On physical examination, she was conscious but in moderate pain. Vital signs were at normal range. Generalized edema was observed throughout the body with pitting edema on both of her lower extremities. Massive ascites with abdominal circumference of 106cm was also observed. Laboratory result showed normocytic normochromic anemia (Hb 11, 50 g/dL, Ht 36,84%). Urine analysis revealed cloudy appearance with the presence of high leukocyte esterase, 16 leukocytes (N: 0-10) and 1+ bacteria. Erythrocyte sedimentation rate was elevated at

20mm/hr along with total bilirubin of 1.4g/dL (N: 0.20-1.0g/dL). Albumin value was 3.01 (N:3.50-5.00g/dL) and potassium levels were 2.8g/dL (N: 3.6-5.0g/dL). Abdominal ultrasound revealed massive ascites and other abdominal organs are within normal size range. Chest roentgenogram revealed a CTR ratio of greater than 50% and increased bronchopulmonary vasculature. Lung bases are cloudy and filled with fluid. A twelve-lead standard electrocardiogram (ECG) showed tachycardia and right axis deviation. Echocardiography revealed severe left ventricular systolic dysfunction with ejection fraction of 30% and dilated left ventricle.

Disease Classification
Cardiomyopathy is classified into two forms2: 1). Primary form disease are caused by damage to the heart muscle as a result of idiopathic or genetic mutations. Examples include hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, isolated ventricular non-compaction, mitochondrial myopathy, eosinophilic endomyocardial disease and endomyocardial fibrosis. 2). Secondary form disease are caused by damage to the heart muscle as a result of insult from other factors such as drugs, autoimmune condition, infections, granulomatous infiltrations, metabolic problems, connective tissue disorders and neuromuscular disorders . In many cases, cardiomyopathy is classified into three morphologic types: dilated, restrictive and hypertrophic due to the differences in their pathophysiology and anatomic features.
Figure 1

Case Definition
Peripartum cardiomyopathy is defined as cardiac failure that occurs (all most be present)3: 1) 2) 3) 4) In the last month of pregnancy or within five months of delivery No identifiable cause of cardiac failure No recognizable heart disease before the last month of pregnancy An ejection fraction of less than 45% or the combination of an M-mode fractional shortening of less than 30% and an end-diastolic dimension greater than 2.7cm/m2.

Clinical Presentation
The early stages of cardiomyopathy are commonly asymptomatic. As the disease progresses which may take months to years after the initial insult, patients commonly classic symptoms of congestive heart failure some of which may be alone or in combination of4: I. II. III. IV. V. VI. VII. VIII. IX. Dyspnea with or without exertion Palpitations and Diaphoresis Angina Ascites Peripheral Edema Pulmonary Edema Unexplained Fatigue Syncope In some cases, sudden death

Laboratory evaluation may also be beneficial in differentiating between the three forms of cardiomyopathy5: Table 1.

Dilated
1). Moderate to marked cardiac silhouette enlargement 2).Pulmonary venous hypertension ST-segment and T-wave abnormalities

Restrictive

Hypertrophic

Chest Roentgenogram

Mild cardiac silhouette enlargement

Mild to moderate cardiac silhouette enlargement

Electrocardiogram

Low voltage, conduction defects 1). Increased left ventricular wall thickness 2). Normal or mildly reduced systolic function

ST-segment and T-wave abnormalities 1). Asymmetric septal hypertrophy 2). Systolic anterior motion (SAM) of the mitral valve

Echocardiogram

Left ventricular dilatation and dysfunction

Cardiac catheterization

1). Left ventricular dilatation and dysfunction 2). Elevated left and open right sided filling pressures 3).Diminished cardiac output

1). Normal or mildly reduced systolic function 2). Elevated left- and right-sided filling pressures

1). Vigorous systolic function 2). Dynamic left ventricular outflow obstruction 3). Elevated left- and right-sided filling pressures

Etiology and Pathogenesis

The major cause of dilated cardiomyopathy is myocardial damage due to prolonged or continuous unknown infection, metabolic problems or exposure to toxic agents. On the other hand, about one third of these patients have familial forms of dilated cardiomyopathy most commonly caused by mutations in genes encoding for sarcomeric proteins of the heart 5. As a result, these abnormal proteins cause contractile dysfunction by impairing the production and/or transmission of force of heart pump. Multiple etiologies are related to the development of dilated cardiomyopathy and they can be seen as listed below:

Arrythmogenic dysplasia Right Ventricular Cardiomyopathy/ Dysplasia

1)Autosomal dominant mutationof Plakophilin-2 (PKP-2) gene 2)Abnormalities in desmosomes causing detachment and myocyte apoptosis and fibrofatty replacement

Peripartum
1)Develop at the last trimester to within five months postpartum 2)Inflammatory myocarditis, immune activation and gestational hypertension

Left Ventricular noncompaction

1)Result from arrest of normal embryogenesis 2)Presence of multiple deep trabeculations or sinusoids that form in the myocardium

Drugs
Neuromuscular Disease
Duchenne Muscular Dystrophy associated with myocyte death. 1)Antineoplastic Agents 2)Anthracyclin derivative 3)Damage to inner mitochondrial membrane

Dilated
Cardiomyopathy

Tako-Tsubo DCM/Stress
1)Ballooning of coronary epicardial coronary vessels 2)Associated with sudden stress or adrenergic surge on cardiac muscle

Alcohol
1)Consuming >90g/day 2)Polymorphism of gene ALDH2 encoding alcohol metabolizing enzyme

Figure 2

Hypertrophic cardiomyopathy is found in about 1 out of 500 of the general population5. The most striking abnormality seen in this disease is diastolic dysfunction which may be detected Doppler tissue imaging and results in elevated LV end-diastolic pressure. The pattern of hypertrophy differs from those caused by aortic stenosis and hypertension as there are a disproportionate and disorganized arrangement of myocytes with disorganization of myofibrillar architecture, along with a variable degree of myocardial fibrosis and thickening of the small intramural coronary arteries6.

Glycogen Storage cardiomyopathy

1)Mutation in the regulatory gamma-2 subunit (PRKAG2) of adenosine monophospateactivated protein kinase (AMPK) 2)Characterized by myocytes with vacuoles in the myocyes that stain for gylcogen in histopathology examination

Friedrich's Ataxia
1)Autosomal recessive spinocerebellar degenerative 2)Inadequate levels of frataxin (protein involved in iron metabolism) 3)Lacking in cellular disarray in histopathology examination.

Cardiac Danon Disease

1)Mutation is an X-linked lysosome-associated membrane (LAMP2) 2)Enlarged ventricular myocytes with Periodic Acid Schiff positive inclusions 3)LV hypertrophy and ventricular pre-excitation

Fabry Disease
1)An X-linked lysosomal storage disease caused by deficiency of lysosomal alpha-galactoside A. 2) Accumulation of glycosphingolipids 3)Associated with AV conduction abnormalities and ventricular tacharrythmias

Hypertrophic
Cardiomyopathy

Figure 3

The hallmark of restrictive cardiomyopathy is abnormal diastolic function due to rigid ventricular walls. At the later stage the disease may impair systolic function as progressive injury occurs to the myocytes. Partial obliteration of the ventricular cavity by fibrous tissue and thrombus are major contributors to the increased resistance in ventricular filling in restrictive cardiomyopathy5.

Cardiac Amyloidosis
1)Deposition of amyloid in cardiac interstitium 2)Heart cells is non-compliant and has a waxy appearance

Eosinophilic endomyocardial disease

1)Loeffler's endocarditis or fibroplastic endocarditis 2)Heart cells that are damaged due to toxic efects of eosinophilic proteins 3)Hepatosplenomegaly and localized eosinophilic infiltration of other organs commonly present

3) Four common symptoms (alone or in combination): diastolic dysfunction, systolic dysfunction, arrythmias and/or orthostatic hypotension

Carcinoid syndrome
1) Endocardial fibrosis, stenosis and regurgitation of tricuspid and/or pulmonary valve

restrictive
Iron-overload cardiomyopathy
1)Associated with frequent blood transfusions 2)Hemoglobinopathy Thalassemia

Cardiomyopathy

Deficiency
1)Thiamine (B1) 2)Electrolytes 3)Selenium

Figure 4

Complications4
A. B. C. D. E. F. Atrial Fibrillation Mitral regurgitation Conduction abnormalities Congestive Heart Failure Stroke or Thromboembolism Hepatomegaly as a result of persistent elevated systemic venous pressure

Management
In general, all patients suffering from congestive heart failure should be treated promptly. It is important to treat the fluid retention with diuretics before initiating an ACE inhibitor or ARB (if patient is intolerant of ACE-inhibitor)6. Beta-blockers should then be started after the ACE inhibitor has been uptitrated. If the patient remains asymptomatic, an aldosterone antagonist, ARB or digoxin may be added as triple therapy. Anticoagulation and antiplatelet therapy may be considered in patients with depressed left 6 ventricular function because these patients are at an increased risk of thromboembolism or stroke . Preferably, warfarin is prescribed in cases of heart failure, chronic or paroxysmal atrial fibrillation, or in patients who have a history of pulmonary emboli, including stroke and transient ischemic attack. Low dose aspirin (75-81mg) is used for the prevention of myocardial infarction and death. Heart Failure treatment during pregnancy In peripartum cardiomyopathy, treatment are focused on halting the sequel of heart failure. Pregnant patients are prescribed medications such as hydralazine and nitrates which can reduce afterload along with digoxin, beta-blockers and loop diuretics6. The use of angiotensin-converting enzyme and angiotensin receptor blocker are contraindicated in pregnancy because they have been associated with fetopathy such as fetal hypotension, oligohydramnios-anuria and renal tubular dysplasia7,8. Pregnant women should also receive anticoagulation therapy as the risk of thromboembolic complications increases due to higher concentrations of factors II, VII, VIII, X and plasma fibrinogen. The therapy are given and should be continued up to 6 weeks postpartum or until a normal left ventricular function is confirmed 3. Warfarin is not used in pregnancy as they can cause spontaneous cerebral hemorrhage when used in the second and third trimester of pregnancy9,10, however unfractionated or low-molecular-weight heparin can safe to use in pregnancy. Heart Failure treatment postpartum Treatment for postpartum cardiomyopathy is identical to those who are nonpregnant and includes the use of ACE inhibitors and ARB. Dosage is one-hald the maximum antihypertensive dose. Selective and nonselective beta-blockers are recommended for peripartum cardiomyopathy6 as they have been proven to improve symptoms, ejection fraction and survival rates. Dosage goal for non-selective beta-blockers such as carvedilol is 25mg twice a day up to 50mg twice a day for larger patients. Selective beta-blockers such as metaprolol succinate 100mg can also be given once a day. Diuretics may be used for symptomatic relief of edema and the use of sprinolactone or digoxin are used in patients who have New York Heart Association class III or IV symptoms. Other proposed therapies include calcium channel antagonists11, statins12, monoclonal antibodies13, interferon beta14,immunoadsorption15, therapeutic apheresis16, and cardiomyoplasty17.

Prognosis
Prognosis of patients with peripartum cardiomyopathy are based on T-Troponin levels, ORS duration and ejection fraction. A troponin-T concentration of more than 0.04ng/mL are predictive of persistent left ventricular dysfunction, a QRS duration of 120ms or more is a risk factor for death and sudden death 18,

while ejection fractions of less than 30% are more indicative of poor left ventricle recovery. Other factors associated with the lack or recovery include an initial left ventricular end-diastolic dimension of greater than 5.6cm, left ventricular thrombus and African American race6. A study on peripartum cardiomyopathy by Elkayam et al 19 reported a two year follow-up that out of 100 patients who had the disease, 54 of them had recovered normal left ventricular fucntion at the end of 2 years, nine people that died and four of them which recieved a heart transplant.

Prevention
Since peripartum cardiomyopathy is a rare form of idiopathic primary myocardial disease with a yet indefinite etiologic cause, prevention are mainly targeted at halting more damage to the dilated heart and these includes medications such as diuretics, beta-blockers ARB and ACE inhibitors. In patients whose left ventricular function has fully recovered, subsequent pregnancy still carries a low risk for developing another sequel of cardiomyopathy20. On the other hand, if left ventricular function has not recovered, the risk of worsening heart failure and long-term systolic dysfunction are high and subsequent pregnancy should be avoided.

References
1. Epidemiology of cardiomyopathy. Clinical Key Elsevier 2012. Retrieved 17 January 2013 2. Elliott P, Andersson B, Arbustini E, et al. Classication of the cardiomyopathies:a position statement from the European Society Of Cardiology Working Group on Myocardial and Pericardial Diseases. European Heart Journal 2008; 29:270276 3. Ramaraj R, Sorell VL. Peripartum cardiomyopathy: disease causes, diagnosis and treatment. Cleveland Clinic Journal of Medicine 2009;76 (5) 4. Baughman KL et al: Braunwalds Heart Disease. Elsevier, Philadelphia, Pennsylvania, 2005 5. Wynne J, Braunwald E: Cardiomyopathy and Myocarditis. Harrisons Cardiovascular Medicine. McGraw-Hill, 2010. 6. Amos AM, Jaber WA, Russell SD. Improved outcomes in peripartum cardiomyopathy with contemporary. American Heart Journal 2006; 152:509513. 7. Pearson GD, Veille JC, Rahimtoola S, et al. Peripartum cardiomyopathy: National Heart, Lung, and Blood Institute and Office of Rare Diseases (National Institutes of Health) workshop recommendations and review. JAMA 2000; 283:11831188. 8. Andrade SE, Raebel MA, Brown J, et al. Outpatient use of cardiovascular drugs during pregnancy. Pharmacologic Epidemiology Drug Safety 2008; 17:240247. 9. Ray JG, Vermeulen MJ, Koren G. Taking ACE inhibitors during early pregnancy: is it safe? Canadian Family Physician 2007; 53:14391440.

10. Clark NP, Delate T, Witt DM, Parker S, McDuffie R. A descriptive evaluation of unfractionated heparin use during pregnancy. Journal of Thrombolysis 2008 11. Narin C, Reyhanoglu H, Tulek B, et al. Comparison of different dose regimens of enoxaparin in deep vein thrombosis therapy in pregnancy. Advanced Therapy 2008; 25:585594. 12. Yuan Z, Kishimoto C, Shioji K. Beneficial effects of low-dose benidipine in acute autoimmune myocarditis: suppressive effects on inflammatory cytokines and inducible nitric oxide synthase. Circulation Journal 2003; 67:545550. 13. Li WM, Liu W, Gao C, Zhou BG. Immunoregulatory effects of atorvastatin on experimental autoimmune myocarditis in Lewis rats. Immunology Cell Biology 2006; 84:274280. 14. Yuan HT, Liao YH, Wang Z, et al. Prevention of myosin-induced autoimmune myocarditis in mice by anti-L3T4 monoclonal antibody. Canadian Journal of Physiology and Pharmacology 2003; 81:8488. 15. Kuhl U, Pauschinger M, Schwimmbeck PL, et al. Interferon-beta treatment eliminates cardiotropic viruses and improves left ventricular function in patients with myocardial persistence of viral genomes and left ventricular dysfunction. Circulation 2003; 107:27932798. 16. Felix SB, Staudt A. Non-specific immunoadsorption in patients with dilated cardiomyopathy: mechanisms and clinical effects. International Journal of Cardiology 2006; 112:3033. 17. Bosch T. Therapeutic apheresisstate of the art in the year 2005. Therapeutic Apheresis and Dialysis 2005; 9:459468. 18. Liu Z, Yuan J, Yanagawa B, Qiu D, McManus BM, Yang D. Coxsackie virus induced myocarditis: new trends in treatment. Expert Review of Anti Infective Therapy 2005; 3:641650. 19. Elkayam U, Akhter MW, Singh H, et al. Pregnancy-associated cardiomyopathy:clinical characteristics and a comparison between early and late presentation. Circulation 2005; 111:20502055. 20. Fett JD, Christie LG, Murphy JG. Brief communication: Outcomes of subsequent pregnancy after peripartum cardiomyopathy: a case series from Haiti. Annals of Internal Medicine 2006; 145:30 34.

Figures:
1. Figure 1. Revised by Malcolm J. Types of Cardiomyopathies". The Merck Manual Home Health Handbook 2008